Glaucoma is a leading cause of blindness with a wide range of clinical presentation. While intraocular pressure (IOP) is considered the most important risk factor for glaucoma, the variability between eyes in sensitivity to IOP is still poorly understood. In recent years, evidence has been accumulating of an association between the susceptibility to glaucoma and the magnitude of the cerebrospinal fluid pressure (CSFP). It has been speculated that this association is due to the forces of CSFP on the posterior aspect of the optic nerve head (ONH). Our hypothesis is that both IOP and CSFP are significant contributors to the biomechanical environment within the ONH. In this framework, an imbalance between IOP and CSFP results in deformations of the tissues of the ONH, particularly on the lamina cribrosa (LC), triggering events such as compromised axoplasmic flow and vascular perfusion, and astrocyte activation that contribute to glaucomatous optic neuropathy. Therefore, understanding the interplay between IOP and CSFP is central to understanding the mechanisms underlying the range of sensitivities to IOP. The long-term goal of this project is to determine the in-vivo effects of IOP and CSFP on the ONH and their interactions, in healthy eyes and in eyes exposed to chronic ocular hypertension, and to identify the characteristics that are best predictors of individual eye sensitivity to these pressures. Advances in optical coherence tomography (OCT) allows us, for the first time, to obtain detailed visualization of the ONH and the LC in-vivo. In primates, we will control the IOP and CSFP while imaging the ONH region with OCT in multiple pressure combinations. Using advanced image processing we will determine the global, sectoral and local pressure-induced tissue deformations, including stretch, compression and shear. Histomorphometry will be used to supplement the in-vivo measurements with parameters not available in vivo. Using statistical modeling and first-principles biomechanics we will develop a mechanistic model of the structural causes underlying individual eye sensitivity to IOP and CSFP. We will determine whether, and which, acute effects of IOP and CSFP are good predictors of chronic IOP-induced changes of the ONH (e.g. tissue stiffening and LC remodeling), and the effects that these changes have on the ONH sensitivity to IOP and CSFP. This project will provide unprecedented information on the in-vivo biomechanics of the ONH and LC. We will be able to identify eye-specific markers indicating eyes at heightened sensitivity to pressure according to their structural features, and biomechanical response to pressure modulation. Integrating experiments and modeling we will be able to predict ONH parameters that cannot be readily measured in conventional settings, reducing the use of invasive procedures. Clarifying the interactions between IOP and CSFP will enable development of evidence-based preventative and treatment interventions for reducing glaucoma morbidity.